Characterisation of a murine model of the late asthmatic response.
Characterisation of a murine model of the late asthmatic response.
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DOI：
10.1186/s12931-017-0541-x
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发表时间：
2017-04-11
影响因子：
5.8
通讯作者：
Birrell MA
中科院分区：
文献类型：
--
作者：
Baker K;Raemdonck K;Snelgrove RJ;Belvisi MG;Birrell MA
哮喘的发病率正在以惊人的速度增长。虽然目前可用的治疗方法是有效的，但也有相关的副作用，它们无法充分控制所有患者亚群的症状。为了了解疾病的发病机制和寻找有效的治疗方法，假说通常在进入临床研究之前在动物模型中进行测试。然而，目前的教条是，动物模型数据往往不能预测临床结果。一个可能的原因是终点测量，如抗原激发诱导的迟发性哮喘反应(LAR)经常用于早期临床开发，但很少用于动物模型系统。由于小鼠通常被选为临床前模型的首选物种，我们想要描述和探索表现出过敏原诱导的LAR的小鼠模型的有效性。C57BL/6小鼠用抗原致敏，然后用相同的抗原局部攻击。用转基因小鼠和一系列药理学工具测定了AlumTM佐剂、糖皮质激素、长效M受体拮抗剂(LAMA)、TRPA1、CD4+和CD8+T细胞、B细胞、肥大细胞和IgE在LAR中的作用。我们的数据显示，与哮喘的其他特征(例如细胞炎症、IgE水平升高和呼吸道高反应性(AHR))不同，LAR需要AlumTM佐剂。此外，LAR似乎对糖皮质激素敏感，需要CD4+T细胞。与其他被研究的物种不同，LAR对LAMA处理不敏感，也不需要TRPA1离子通道，这表明该物种的LAR不涉及呼吸道感觉神经。此外，数据表明CD8+T细胞和肥大细胞-B-细胞-IgE轴在该小鼠模型中似乎具有保护作用。总而言之，我们可以得出结论，该模型确实具有类固醇敏感、CD4+T细胞依赖、变应原诱导的LAR。然而，总的来说，我们的数据质疑在未来哮喘治疗评估中使用LAR的小鼠临床前模型的有效性。本文的在线版本(doi：10.1186/s12931-0170541-x)包含补充材料，授权用户可以使用。
The incidence of asthma is increasing at an alarming rate. While the current available therapies are effective, there are associated side effects and they fail to adequately control symptoms in all patient subsets. In the search to understand disease pathogenesis and find effective therapies hypotheses are often tested in animal models before progressing into clinical studies. However, current dogma is that animal model data is often not predictive of clinical outcome. One possible reason for this is the end points measured such as antigen-challenge induced late asthmatic response (LAR) is often used in early clinical development, but seldom in animal model systems. As the mouse is typically selected as preferred species for pre-clinical models, we wanted to characterise and probe the validity of a murine model exhibiting an allergen induced LAR. C57BL/6 mice were sensitised with antigen and subsequently topically challenged with the same antigen. The role of AlumTM adjuvant, glucocorticoid, long acting muscarinic receptor antagonist (LAMA), TRPA1, CD4+ and CD8+ T cells, B cells, Mast cells and IgE were determined in the LAR using genetically modified mice and a range of pharmacological tools. Our data showed that unlike other features of asthma (e.g. cellular inflammation, elevated IgE levels and airway hyper-reactivity (AHR) the LAR required AlumTMadjuvant. Furthermore, the LAR appeared to be sensitive to glucocorticoid and required CD4+ T cells. Unlike in other species studied, the LAR was not sensitive to LAMA treatment nor required the TRPA1 ion channel, suggesting that airway sensory nerves are not involved in the LAR in this species. Furthermore, the data suggested that CD8+ T cells and the mast cell—B-cell - IgE axis appear to be protective in this murine model. Together we can conclude that this model does feature steroid sensitive, CD4+ T cell dependent, allergen induced LAR. However, collectively our data questions the validity of using the murine pre-clinical model of LAR in the assessment of future asthma therapies. The online version of this article (doi:10.1186/s12931-017-0541-x) contains supplementary material, which is available to authorized users.